1. Field of the Invention
The present invention relates generally to the fields of biology, cardiology, physiology and molecular biology. More particularly, it concerns cardiovascular disease and hypertension. Specifically, the invention relates to the use of the Calcium-Calmodulin Kinase II (CaMKII) binding domain with histone deactylase (HDAC) 4, as well as the use of the HDAC dimerization domain, to treat or prevent cardiovascular diseases and hypertension, or to screen for compounds that could be used to treat or prevent cardiovascular diseases and hypertension.
2. Description of Related Art
Hypertension, a highly underdiagnosed problem in the world today, is a frequent precursor of a myriad of syndromes including cardiac hypertrophy, many renal diseases, and congestive heart failure. Uncontrolled or undiagnosed high blood pressure, or hypertension, can be basically described as the force of blood against the artery walls being too strong. High blood pressure can damage the arteries, heart, and kidneys, and lead to atherosclerosis and stroke. Hypertension is called a “silent killer” because it does not cause symptoms unless it is severely high and causes major organ damage if not treated.
Heart failure, cardiac hypertrophy and other cardiovascular diseases can occur as a result of hypertension or can lead to the development of hypertension, and the symptoms manifested may include the left ventricle being hypertrophied and dilated, left ventricular diastolic dysfunction, and indices of systolic function, such as ejection fraction, being reduced. Untreated high blood pressure can also damage the delicate lining of the blood vessels. Once damaged, fat and calcium can easily build up along the artery wall, forming a plaque. The blood vessel becomes narrowed and stiff (atherosclerosis), and blood flow through the blood vessel is reduced. Over time, decreased blood flow to certain organs in the body can cause damage, leading to a variety of diseases such as heart disease, heart attack, abnormal heartbeat, stroke, kidney (renal) failure, peripheral arterial disease, and eye damage (retinopathy).
Signaling by CaMKII has been implicated in such pathological cardiac growth, but the downstream effectors of CaMKII action remain poorly defined. CaM kinases have, however, been shown to interact with and modulate signaling through the HDAC/myocyte enhancer factor-2 family (MEF2) cascade (Davis et al., 2003). MEF2's are a family of transcription factors that interact with HDACs and they have been previously implicated in cardiovascular diseases, especially those diseases associated with abnormal intracellular calcium levels (like those which were initially found to involve CaMKII's). For example, a variety of stimuli can elevate intracellular calcium, resulting in a cascade of intracellular signaling systems or pathways, including calcineurin, CaM kinases, PKC and MAP kinases. All of these signals activate MEF2 and can result in activation of an unwanted gene program known as the fetal gene program. However, it is still not completely understood how the various signal systems exert their effects on MEF2 and modulate its signaling. In work attempting to understand MEF2 and cardiovascular disease, it was shown that certain HDACs are involved in modulating MEF2 activity (McKinsey et al., 2000) and it has been previously shown by the inventors that HDACs are intimately involved in regulation of cardiac gene expression (McKinsey & Olson, 2004).
Seventeen different HDACs have been cloned from vertebrate organisms and have been separated into three different classes. All share homology in the catalytic region. Histone acetylases (HATs) and deacetylases play a major role in the control of gene expression. The balance between activities of HATs, and HDACs determines the level of histone acetylation and further, gene expression. Acetylated histones cause relaxation of chromatin and activation of gene transcription, whereas deacetylated chromatin is generally transcriptionally inactive. HDAC4 and 5, for example, have now been shown to dimerize with MEF2 and repress the transcriptional activity of MEF2, which can be beneficial to the heart and the peripheral vasculature (McKinsey et al., 2000).
Years of research have also highlighted the important role of HDACs in cancer biology, demonstrating a role for HDACs in a diversity of disease settings. In fact, various inhibitors of HDACs are being tested in the clinic for their ability to induce cellular differentiation and/or apoptosis in cancer cells (Marks et al., 2000). Such inhibitors include suberoylanilide hydroxamic acid (SAHA) (Butler et al., 2000; Marks et al., 2001); m-carboxycinnamic acid bis-hydroxamide (Coffey et al., 2001); and pyroxamide (Butler et al., 2001). These studies were initially summarized as indicating “that the hydroxamic acid-based HPCs, in particular SAHA and pyroxamide—are potent inhibitors of HDAC in vitro and in vivo and induce growth arrest, differentiation, or apoptotic cell death of transformed cells . . . [and thus] are lead compounds among the family of hydroxamic acid-based HPCs and are currently in phase I clinical trials” (Marks et al., 2000). Since that time, a multitude of companies have initiated research programs into the anti-tumor effects of HDAC inhibitors. More on point, HDAC inhibitors have been shown to be anti-hypertrophic and capable of treating heart failure (U.S. Pat. No. 6,706,886 and U.S. patent application Ser. No. 10/801,985, hereinafter incorporated in their entirety by reference). To date, however, no therapeutic approach for cardiovascular disease has supplanted the need for newer or better therapies.